Entrapment of biological materials, such as cells, is a technique that has been used for various ends. Exemplary of the patent literature in this area are U.S. Pat. No. 6,303,151 (Asina, et al.); U.S. Pat. No. 6,224,912 (Asina, et al.); U.S. Pat. No. 5,888,497 (Jain, et al.); U.S. Pat. No. 5,643,569 (Jain, et al.), and RE 38,027 (Jain, et al.), all of which are incorporated by reference in their entirety. This family of related patents shows that cancer cells and islets can be entrapped in a biocompatible matrix, such as agarose, agarose/collagen mixtures, and agarose/gelatin mixtures, and then be coated with agarose. The resulting, entrapped cells produce materials which, inter alia, diffuse out of the permeable biocompatible matrices in which they are retained, and have useful biological properties. In the case of islets, insulin is produced. In the case of cancer cells, material diffuses from the matrix, and this material has an effect on the growth and proliferation of cancer cells. As review of the '912 and '151 patents, cited supra, will show, this effect crosses species, i.e., entrapped or encapsulated cancer cells from a given species produce material that inhibits the growth and/or proliferation of cancer cells from other species, as well as the species from which the cancer cells originated.
Additional examples of entrapment techniques include, e.g., U.S. Patent No. 5,227,298 (Weber, et al.); U.S. Pat. No. 5,053,332 (Cook, et al.); U.S. Pat. No. 4,997,443 (Walthall, et al.); U.S. Pat. No. 4,971,833 (Larsson, et al.); U.S. Pat. No. 4,902,295 (Walthall, et al.); U.S. Pat. No. 4,798,786 (Tice, et al.); U.S. Pat. No. 4,673,566 (Goosen, et al.); U.S. Pat. No. 4,647,536 (Mosbach, et al.); U.S. Pat. No. 4,409,331 (Lim); U.S. Pat. No. 4,392,909 (Lim); U.S. Pat. No. 4,352,883 (Lim); and, U.S. Pat. No. 4,663,286 (Tsang, et al.). All of these references are incorporated by reference.
Entrapment does not always result in a positive impact on the entrapped cells. For example, see Lloyd-George, et al., Biomat. Art. Cells & Immob. Biotech., 21(3):323-333 (1993); Schinstine, et al., Cell Transplant, 41(I):93-102 (1995); Chicheportiche, et al., Diabetologica, 31:54-57 (1988); Jaeger, et al., Progress In Brain Research, 82:41-46 (1990); Zekorn, et al., Diabetologica, 29:99-106 (1992); Zhou, et al., Am. J. Physiol., 274:C1356-1362 (1998); Darquy, et al., Diabetologica, 28:776-780 (1985); Tse, et al., Biotech. & Bioeng., 51:271-280 (1996): Jaeger, et al., J. Neurol., 21-469-480 (1992); Hortelano, et al., Blood, 87(12):5095-5103 (1996): Gardiner, et al., Transp. Proc., 29:2019-2020 (1997). All of these references are incorporated by reference.
None of the references discussed supra deals with the class of cells known as stem cells, including embryonic stem cells.
One definition of stem cells, advanced by Reya, et al., Nature, 414:105-111 (2001), incorporated by reference, refers to stems cells as cells which have the ability to perpetuate themselves through self renewal and to generate mature cells of particular tissues via differentiation. One can obtain different types of stem cells, including neural, hematolymphoid, myeloid, and other types of stem cells from various organs. These all have potential to develop into specific organs or tissues. Certain stem cells, such as embryonic stem cells, are pluripotent, in that their differentiation path has not been determined at all, and they can develop into various organs and tissues.
The discussions of the various therapeutic uses to which stem cells may be put are well known, and need not be discussed here. It is worth mentioning, as it bears on the invention described herein, that stem cells are very uncommon, their purification and separation from other cell types is laborious and difficult, and stem cells will differentiate into mature cell unless treated in some way to prevent this.
It has now been found that entrapment procedures, in line with those disclosed by Jain et al. and Iwata et al., Journ. Biomedical Material and Res., 26:967 (1992) affect stem cells in a very desirable way. To elaborate, entrapped stem cells produce materials which inhibit proliferation of various cell types, including stem cells and cancer cells. The effect of this material crosses species lines. Further, it has been found that stem cells, when entrapped as is described herein, retain their differentiating abilities, including their pluripotentiality, for an indefinite period of time.
These features, as well as others, will be seen in the disclosure which now follows.